Apparatus, system, and method for the objective evaluation of corporeal pain and autonomic nerve dysfunction

ABSTRACT

Various methods and machines have been used in the past to measure electrical characteristics of living tissue for purpose of locating an area of abnormal nervous system activity. However, whereas prior art methodologies merely allow for the detection of pain, the apparatus, system and method of the present invention allow for the objective assessment of autonomic nerve function and/or pain severity. As such, the present invention finds utility not only the initial diagnosis, including the early diagnosis of generally asymptomatic autonomic dysfunction, but also the on-going treatment of any disease, disorder or injury associated therewith. To that end, the apparatus, system and method of the present invention allows medical practitioners to non-invasively and quantitatively distinguish the organic from the psychosomatic and legitimate pain patients from drug seekers and opioid addicts, as well as to directly and objectively compare the efficacy of different drug regimens and therapy protocols.

PRIORITY

This application claims priority to U.S. patent application Ser. No. 15/842,091 filed Dec. 14, 2017, which, in turn, claims the benefit of U.S. Provisional Application Ser. No. 62/434,169 filed Dec. 14, 2016, the contents of which are hereby incorporated by reference in their entirety.

TECHNICAL FIELD OF THE INVENTION

The present invention relates generally to the correlation between electrical tissue parameters, such as skin conductance, with sympathetic and parasympathetic nerve function (and dysfunction). More particularly, the present invention relates to an apparatus, system and method for the non-invasive sudomotor assessment of autonomic nerve function (and dysfunction) that, in turn, facilitates the diagnosis and objective evaluation of any underlying, often asymptomatic, disorder, disease or injury associated with the measured nerve parameters as well as the direct and objective comparison different therapy protocols and drug regimen and the efficacy thereof. The apparatus, system and methods of the present invention may also be applied to the non-invasive assessment of corporeal pain, including an objective measurement of pain severity that, in turn, finds utility not only in the diagnosis and treatment of any underlying disorder, disease or injury associated with the measured pain levels but also in determining the appropriate drug and dosage regimen, in distinguishing organic pain from psychosomatic pain and legitimate pain patients from drug seekers and opioid addicts, and in directly and objectively comparing the efficacy of different therapy protocols and drug regimen.

BACKGROUND OF THE INVENTION

During the latter portion of the twentieth century, researchers made significant contributions to the measurement of perspiration and its relationship to the sympathetic portions of the human nervous system. It is accepted that moist skin is associated with the ability to conduct electricity more readily than dry skin, the former having a lower resistance to electrical flow. When the nerve supply to the skin is interrupted, skin moisture drops, conductance falls, and the skin resistance level rises.

Early investigations of the variability of skin electrical responses created by changing parameters of stimulation indicated that the measurement of conductance levels, and not responses, would provide more stable results. This removed the need for any external or internal stimulation and thus created an improvement in methodology.

Although this technology was originally intended for the measurement of human skin conductance, such electrical assessment has also been used for other types of deep tissue, e.g. in the fields of marine biology and plant physiology. Therefore, the term Selective Tissue Conductance (STC) was adopted as being more appropriate for the broad range of biological materials that could be evaluated with this technology.

There are also two other methodological differences that separate Selective Tissue Conductance technology from other forms of skin conductance measurement, namely Spatial Selectivity and Temporal Selectivity.

Early methods of measuring skin conductance or resistance often consisted of passing an electrical test current between a static reference electrode and a roving or exploring electrode which was moved over the areas of the skin to be assessed. If it happened that the reference and roving electrodes were placed on opposite sides of the body, then the electrical flow would transverse the body creating transcorporeal currents. If this path flowed through electrically sensitive organs, e.g. the heart, theoretical if not actual risks of arrhythmia would be increased.

In U.S. Pat. No. 4,697,599, the details of which are hereby incorporated by reference, Woodley et al. disclose a selective tissue conductance meter that overcomes the problem of spatial selectivity by using a fixed, bipolar concentric electrode that is simply pressed against the skin surface. The concentric electrode disclosed in the '599 patent consists of a central contacting electrode and an outer ring electrode that surrounds the center electrode. Additionally, a circular gap filled with an electrical insulating material is provided between the center electrode and the outer ring electrode. Consequently, when the concentric electrode is pressed against the skin and an electrical test current is discharged from the center electrode, the path of the electrical test current is restricted so that the test current travels from the center contact electrode to the outer ring electrode by volume conduction through only the superficial layers of the skin, thus preventing the possibility of producing a trans-corporeal current.

More specifically, the device disclosed in the '599 patent is a diagnostic device capable of measuring the conductance of human or animal tissue that includes a housing capable of being held in one hand by the user of the device and a concentric electrode mounted on the exterior of the housing. An electric circuit is located in the housing and is connected to the concentric electrode to produce an electrical signal having a pulse frequency that varies directly according to the conductance of the human or animal tissue placed in contact with the electrode. The electric circuit includes a voltage to frequency converter, having an oscillator with logarithmic output, so that the pulse frequency varies logarithmically according to the conductance measured by the electrodes. The logarithmic output permits a wide range of tissue conductances to be measured. A source of low voltage power is connected to the circuit and a detector is provided for detecting the electrical signal to permit the user to know the pulse frequency of the signal.

Almost ten years later, in U.S. Pat. No. 5,897,505, Feinberg et al. describe an improvement on the Woodley construction, wherein the selective tissue conductance apparatus is modified to include a thermography sensor. However, while the prior art enables identification of the presence of pain in one or more certain locations, it yet still fails to enable the automated measurement and objective assessment of the degree of the pain and thus the severity of the underlying injury, disease or disorder. Accordingly, there is a need in the art and the present invention aims for an apparatus, system, and method for the objective evaluation of corporeal pain.

There is a further need in the art for means and methods for the objective evaluation and clinical assessment parasympathetic (P) and sympathetic (S) nerve function, with the goal of identifying instances of P & S imbalance associated with often asymptomatic autonomic nerve dysfunction (AD), and, ultimately, diagnosing and treating the underlying root cause(s) said dysfunction. The present invention addresses this deficiency by providing an apparatus, system, and method that utilizes electrical tissue parameters, such as skin conductance and resistance, as an index of autonomic nerve function.

SUMMARY OF THE INVENTION

A primary goal of the present invention is to provide an apparatus, system and method that allows for the objective evaluation and assessment of patient/subject pain, which, in turn, can be used to identify and characterize the underlying injury, disease or disorder and determine an appropriate therapy, including the adjustment, addition or elimination of chemical, electrical, or physical therapies and/or therapeutic devices.

Another goal of the present invention is to provide an apparatus, system and method that allows for the objective evaluation and assessment of autonomic nerve function (and dysfunction), which, in turn, can be used to identify and characterize an underlying injury, disease or disorder and determine an appropriate therapy, including the adjustment, addition or elimination of chemical, electrical, or physical therapies and/or therapeutic devices.

Illustrative aspects and embodiments of the present invention in accordance with the foregoing objective are as follows:

One objective of the present invention is to provide a hand-held, low-voltage, cost effective diagnostic device for measuring selective tissue conductance, and optionally other physiological parameters, for the independent, simultaneous sudomotor assessment of P and S activity, which, in turn, enables customized and individualized healthcare. For example, physicians may utilize the devices and methods disclosed herein to detect and document both the presence and degree of P & S imbalance, which, in turn, is a hallmark of (often asymptomatic) AD. When significant anomalies are observed, measured, and evaluated, and optionally coupled with other physiological and/or biochemical parameters, the physician may select a particular therapy based on this information and titrate it to the individual's needs based on objective measures of P and S activity and autonomic sympathovagal balance (SB). A normal or ideal SB for an individual patient may then be titrated using common mediations, including beta-blockers, anti-hypertensives, anti-cholinergics, bronchodilators, vasodilators, vasopressors, etc. Maintaining normal SB, which, in turn, is a hallmark of balanced P and S activity, reduces morbidity and mortality risk, promotes wellness, and reduces healthcare costs. Thus, the automated clinical monitoring and sudomotor assessment of P and S activity enabled by the present invention supports evidence-based and value-based medicine and comparative effectiveness benefit.

Low cost, independent, simultaneous P and S monitoring in accordance with the present invention can be used to identify, differentiate, and document patient response to disease and therapy, thereby enabling both early diagnosis of asymptomatic disease and therapy modification prior to development of co-morbidities. Differentiating specific P and S dysfunctions guides therapy selection, particularly when coupled with other physiological analyses, thereby minimizing trial and error. P and S monitoring in accordance with the present invention also provides physicians with more sensitive, quantifiable measures of their patients P and S levels of activity, which, in turn, can serve as an index of autonomic function and dysfunction (AD), which, in turn, can serve as an early stage indicator of asymptomatic autonomic neuropathy which, absent therapeutic intervention, can lead to chronic and irreversible end-organ disease.

For example, in hypertensives, diabetics, or other chronic disease patients, early detection of cardiovascular autonomic neuropathy (CAN) through P and S scanning enables early intervention that, in turn, reduces medication load and hospitalizations due to complications of heart disease. In hypertensives, it can reduce the amount of, and need for long term therapy, associated co-morbidities, and hospitalizations due to stroke, aneurysms, kidney disease, and heart diseases. Evidence suggests that these measures also detect these changes sooner than other measures. This is particularly useful, especially given that reversing poor P and S results leads to improved outcomes and that slowing P and S decline reduced morbidity and mortality, improving quality of life.

Another objective of the present invention is to provide a hand-held, low-voltage, cost effective diagnostic device for measuring selective tissue conductance, and optionally other physiological parameters, for the sympathetic sudomotor assessment of corporeal pain that addresses one or more art-recognized problems and/or drawbacks of prior art alternatives. To that end, in the context of the present invention, the diagnostic device of the present invention is generally characterized by a sensor head and associated device housing, wherein the sensor head includes, at a minimum, a pair of spaced electrodes (i.e., a bipolar electrode assembly) that may be applied to the skin to measure and quantify the level of conductance therein, and the device housing contains the requisite power and circuitry components to enable activation of the one or more sensor head components and transduction of their respective signals to an output that may be correlated to pain, abnormal sensation, or sympathetic nerve dysfunction.

Prior art instruments that utilize a fixed electrode require the user to use great care in accurately placing the instrument against the patient's skin to assure proper uniform contact. This requires that the instrument always be perpendicular to the surface of the skin. Consequently, if not aligned properly, the instrument will provide an erroneous reading. Moreover, ensuring that the instrument is properly aligned when placing the electrode on parts of the body that are curved or contoured, or in places difficult to reach, is particularly problematic. Thus, to address alignment problems present in certain prior art alternatives, the present invention provides the hand-held, low-voltage diagnostic device of the present invention with an optional flexible coupling connecting sensor head to device housing. In preferred embodiments, this coupling may take the form of an articulated, pivoting base for mounting the sensor head to the device housing. For example, the device may include a ball-and-socket type coupling that allows the base of the sensor head to pivot and/or rotate freely to assure proper uniform tissue contact. In one preferred embodiment, the base is provided with a curved or ball type surface that is pivotably received in a mating socket provided on the distal neck portion of the device housing. In an alternate preferred embodiment, the coupling components are reversed. In either case, the free pivoting movement causes the sensor head to automatically move into a properly aligned perpendicular orientation when placed against the skin.

Prior art instruments that utilize permanently installed sensor heads can be problematic as, during use, the permanent electrode can become contaminated with skin oils, moisture, or other contaminates that case errors in the skin conductance measurements. In addition, some clinical procedures require cleaning and disinfecting of the electrodes prior to use on the patient. Cleaning and disinfecting using normal aqueous or alcohol base solutions add additional surface conductivity unless the electrode is properly dried to remove the residual moisture (which also can cause erroneous measurements). Accordingly, to address the drawbacks of the permanently installed sensor head, it is an object of the present invention to manufacture the sensor head as a replaceable, detachable bipolar electrode assembly of sufficiently low cost that may be used either as an interchangeable electrode (allowing for proper sterilization and drying). Alternatively, the sensor head may be manufactured as a disposable product.

In certain embodiments of the present invention, the sensor head can be readily and securely attached to (and detached from) the device housing with each procedure and/or test subject, for example via a screw-in type mounting with spring loaded contact pins to complete the measurement circuit. Alternatively, the present invention contemplates a sensor head that can be physically separated from the device housing, thereby allowing it to be worn by a test subject over a period of time and configured for single and/or continuous monitoring and measurement. In this latter embodiment, the sensor is optionally provided with means to record measurements, such as an integral or on-board memory chip or memory card, and/or means to transmit recorded measurements to the hand-held housing, or, alternatively, directly to a local or remote computer system, database or physician. It may further be optionally configured to directly or indirectly coordinate with or connect to one or more preset ports on a standard laptop computer, smartphone, or tablet.

Many selective tissue conductance meters of the prior art use a direct (DC) current method wherein a small DC voltage is applied between the outer ring and center core of the concentric bipolar electrode assembly. As noted above, the amount of current measured between the two parts of the electrode is proportional to the skin conductivity. However, a problem with the DC current method is that, as the DC potential is applied to the skin or other body tissue, an iontophoresis effect is produced in which the current flow between the electrodes increases over time, thus producing progressively increased measurement values based upon the duration of the application of the DC currently. Consequently, in the context of DC-based measurements, controlling the time interval is critical for obtaining consistent results. However, the present invention eliminates this problem in certain preferred embodiments by utilizing alternating current (AC), more particularly a high frequency (1 to 100 kHz) AC signal to measure the current between the respective components of the bipolar electrode assembly. This eliminates the iontophoresis effect caused by the use of a DC current. Accordingly, in the context of the present invention, time of measurement is not a critical variable and thus measurements obtained are more consistent and accurate.

One objective of the present invention is to provide a multifunctional diagnostic device in which the sensor head is outfitted with multiple sensors for measuring multiple physiological parameters. For example, in one preferred embodiment, the sensor head and/or device housing optionally include other sensors such as (a) thermography cameras and optical infrared scanners to assess the heat and temperature of the affected region; (b) sweat-based glucose, lactate and theophylline biosensors that enable non-invasive transdermal scoring of analyte concentration in tissue, particularly muscle tissue; (c) pulse-oximeters to allows for measurement of oxygen saturation levels and assess pre- and post-flow to the affected region; (d) ultrasonic sensors and transducers that allow a medical practitioner to assess viability and recovery of muscle tissue.

In certain embodiments, the device housing may outfitted with liquid crystal display and optionally an onboard microprocessor and/or memory card or other storage means to allow for collected data to be temporarily stored, or recalled/displayed, until it can be downloaded (or uploaded) to a remote system. Alternatively, the connection between diagnostic device and associated microprocessor device can be wireless, using either short-range signal (such as a Bluetooth® or LAN network) or a long-range digital or cellular network to transfer data, thereby allowing the computer and the treating physician to be either local or remote. The onboard, local or remote microprocessor can record, transcribe and/or analyze specific measurements and/or enable local or remote analysis and diagnosis.

As noted above, in certain embodiments, the device housing can be “smart”, i.e., outfitted with a programmable computer chip or other complex microprocessing components that enable on-board programming and analysis. Alternatively, the device may be a simplified “dummy” device that receives all its programming instructions from a remote microprocessor, such as a laptop computer, tablet or smartphone. So as to reduce user error, in a preferred embodiment, the device housing is outfitted with a display screen that allows the user to cycle through a menu of pre-programmed operating modes and modules, more preferably options that walk the medical practitioner through the requisite set-up, initialization, measurements and/or recordation processes.

In certain preferred embodiment, the components of the diagnostic device may be powered by a pre-charged power source, such as one or more AA or 9-volt batteries. In an alternate embodiment, the diagnostic device can utilize a rechargeable power source, for example, a rechargeable lithium-ion battery, and optionally coupled with requisite charging accessories such as a charging cord, adapter and/or charging cradle.

It is yet another objective of the present invention to provide a kit for measuring selective tissue conductance, and optionally other physiological parameters, for the sympathetic sudomotor assessment of corporeal pain that includes a diagnostic device as described above coupled with:

-   -   one or more pre-powered or rechargeable batteries and associated         charging accessories;     -   one of more audio output devices such as wired or wireless         earphones, headphones, and/or external speakers;     -   one or more disposable sensor heads;     -   one or more memory cards or memory chips for locally storing         data on the diagnostic device;     -   one or more cables for connecting the diagnostic device of the         present invention to microprocessing device such as a laptop         computer, a tablet, smartphone, or external hard drive;     -   requisite analysis and/or report-writing software to facilitate         subject evaluation; and/or     -   written instructions to ensure proper operation.

Yet another objective of the present invention is to provide a series of pre-programmed montages to automate measurement intake for specific injuries and/or tissue types and ensure consistency. For example, the montage may comprise a grid or pattern of vertical and horizontal lines that form four adjacent quadrants of equal size, each of which includes an equal number of aligned measurement sites that are mirrored in adjacent horizontal, vertical and diagonal quadrants so as to enable ready comparison.

In one aspect, the present invention provides an apparatus, system and method that allows for the measurement, recording and analysis of skin conductance measurements so as to objectively evaluate autonomic nerve function and sensory nerve pain, including an assessment of the degree of pain (if any). As noted above, in the context of the present invention, readings at particular locations are compared to normative or baseline measurements. The degree to which a particular reading exceeds an associated “normal” reading determines not just the presence of pain in the noted location but the degree of pain, and, by extension, the severity of the underlying injury, disease or disorder. In preferred embodiments, the present invention utilizes the above-noted pre-programmed montages to automate multiple readings within a particular region of the body. Results are then compared (a) between sides along horizontal lines and (b) between proximal and distal regions measured along vertical lines. By comparing across quadrants, the physician can identify asymmetrical reading(s) and correlate the location of such asymmetry with the degree of pain involved and thus the severity of any underlying injury, disease or disorder. In this manner, the subject acts as his or her own control.

In an alternate embodiment, asymmetrical locations may be identified by comparison to (a) a subject's current readings (e.g., by comparing to a mirrored bilateral equivalent); (b) a subject's prior readings (e.g., from a previous assessment, potentially before the onset of therapy); or (c) a normative data set of “normal” and “pain” patients, optionally further divided and characterized according to sex, age, injury, and body part involved.

It is a further objective of the present invention to provide for the creation of a database that includes a normative set of patient data and/or individualized patient data that may be used by the medical practitioner to identify the presence of a particular nerve disorder, characterize its severity and/or track progress over time. In a preferred embodiment, this database enables the comparison of a pre-injury baseline to a post-injury measurement to distinguish physical injury from psychosomatic pain. Also enabled is the comparison of pain relief afforded from different medications and/or therapies (e.g., opioid vs. non-opioid) and the correlation of raw data/sympathetic parameters to a particular diagnosis and/or therapy.

In yet another aspect, the present invention incorporates software and programming to automate two-point discrimination for assessment of nerve injury and recovery in an affected region.

These and other aspects are accomplished in the invention herein described. Further objects and features of the invention will become more fully apparent when the following detailed description is read in conjunction with the accompanying figures and examples. However, it is to be understood that both the foregoing summary of the invention and the following detailed description are of a preferred embodiment, and not restrictive of the invention or other alternate embodiments of the invention. In particular, while the invention is described herein with reference to a number of specific embodiments, it will be appreciated that the description is illustrative of the invention and is not constructed as limiting of the invention.

BRIEF DESCRIPTION OF THE FIGURES

Various aspects and applications of the present invention will become apparent to the skilled artisan upon consideration of the brief description of figures and the detailed description of the present invention and its preferred embodiments that follows:

FIG. 1A is a photograph depicting a top-down view of an illustrative embodiment of a diagnostic device (100) of the present invention.

FIG. 1B is a photograph depicting a perspective view of the diagnostic device (100) of FIG. 1A.

FIG. 2A is a plan view of the diagnostic device (100) of FIG. 1A.

FIG. 2B is a plan view of a wired earphone that can connect to the diagnostic device (100) of FIG. 1A.

FIG. 2C is a plan view of a connecting cable that serves to connect the diagnostic device (100) of FIG. 1 A.

FIG. 2D is a plan view of a pair of disposable AA batteries that serve as the power source for the diagnostic device (100) of FIG. 1A.

FIG. 3A is a side-elevational view of the underside diagnostic device (100) of FIG. 1A, with battery cover (56) removed.

FIG. 3B is a side-elevational view of the underside of the diagnostic device (100) of FIG. 1A, with proximal battery cover (56) attached and distal electrode (4) removed.

FIG. 3C is an expanded view of the objects of FIG. 3A at location A.

FIGS. 3D and 3E present alternate sensor heads embodiments tailored for veterinary applications.

FIG. 4 is a loop illustration of the different operating modes and utilities that may programmed into a diagnostic device of the present invention.

FIG. 5 depicts an illustrative display screen for a diagnostic device of the present invention, in “Ready” or “Manual” Mode.

FIG. 6 depicts an illustrative display screen for a diagnostic device of the present invention, in “Procedure” Mode.

FIG. 7 depicts an illustrative display screen for the “Review” utility in a diagnostic device of the present invention.

FIG. 8 depicts an illustrative display screen for the “Clear” utility in a diagnostic device of the present invention.

FIG. 9 depicts an illustrative display screen for the “Time/Date Setting” utility in a diagnostic device of the present invention.

FIG. 10 depicts an illustrative display screen for the “Volume” utility in a diagnostic device of the present invention.

FIG. 11 depicts a typical 6×6 matrix, with 6 rows and 6 columns, common to the montage procedures of the present invention and a convention used for numbering of each of measurement sites.

FIG. 12 depicts the 6×6 matrix of measurement sites as well as measurement sequence for assessment of upper facial tissue, designated as preset montage S01 (UPR-FACE).

FIG. 13 depicts the 6×6 matrix of measurement sites as well as measurement sequence for assessment of anterior neck tissue, designated as preset montage S02 (ANT-NECK).

FIG. 14 depicts the 6×6 matrix of measurement sites as well as measurement sequence for assessment of chest tissue, designated as preset montage S03 (CHEST).

FIG. 15 depicts the 6×6 matrix of measurement sites as well as measurement sequence for assessment of abdominal tissue, designated as preset montage S04 (ABDOMEN).

FIG. 16 depicts the 6×6 matrix of measurement sites as well as measurement sequence for assessment of cervical spinal tissue, designated as preset montage S05 (C-SPINE).

FIG. 17 depicts the 6×6 matrix of measurement sites as well as measurement sequence for assessment of thoracic spinal tissue, designated as preset montage S06 (TH-SPINE).

FIG. 18 depicts the 6×6 matrix of measurement sites as well as measurement sequence for assessment of lumbosacral spinal tissue, designated as preset montage S07 (LS-SPINE).

FIG. 19 depicts the 6×6 matrix of measurement sites as well as measurement sequence for assessment of the anterior of the upper arms, designated as preset montage S08 (UPARM-AN).

FIG. 20 depicts the 6×6 matrix of measurement sites as well as measurement sequence for assessment of the posterior of the upper arms, designated as preset montage S09 (UPARM-PO).

FIG. 21 depicts the 6×6 matrix of measurement sites as well as measurement sequence for assessment of the anterior of the forearms, designated as preset montage S10 (FRARM-AN).

FIG. 22 depicts the 6×6 matrix of measurement sites as well as measurement sequence for assessment of the posterior of the forearms, designated as preset montage S11 (FRARM-PO).

FIG. 23 depicts the 6×6 matrix of measurement sites as well as measurement sequence for assessment of the palmar and dorsal surfaces of the hands, designated as preset montage S12 (HANDS).

FIG. 24 depicts the 6×6 matrix of measurement sites as well as measurement sequence for assessment of the anterior of the thighs, designated as preset montage S13 (THIGH-AN).

FIG. 25 depicts the 6×6 matrix of measurement sites as well as measurement sequence for assessment of the posterior of the thighs, designated as preset montage S14 (THIGH-PO).

FIG. 26 depicts the 6×6 matrix of measurement sites as well as measurement sequence for assessment of anterior of the lower legs, designated as preset montage S15 (LOLEG-AN).

FIG. 27 depicts the 6×6 matrix of measurement sites as well as measurement sequence for assessment of posterior of the lower legs, designated as preset montage S16 (LOLEG-PO).

FIG. 28 depicts the 6×6 matrix of measurement sites as well as measurement sequence for assessment of the plantar and dorsal surfaces of the feet, designated as preset montage S17 (FEET).

FIG. 29 is a diagrammatic representation of the autonomic nervous system (ANS) and its two branches, the parasympathetic and sympathetic nervous systems. Note that the ANS controls all other organs and precedes those organs. Since symptoms generally do not occur until end-organ dysfunction, autonomic dysfunction is largely asymptomatic and thus difficult to detect in the early stages.

FIG. 30 depicts the four P and S imbalances. These are the only four abnormal autonomic states.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention relates to new and improved hand-held, low-voltage diagnostic devices for measuring selective tissue conductance, and optionally other physiological parameters, for the sympathetic sudomotor assessment of corporeal pain as well as software and hardware systems and methods associated therewith that enable the objective evaluation and assessment of patient pain, which, in turn, can be used to identify and characterize the underlying injury, disease or disorder and determine an appropriate therapy.

The present invention also relates to new and improved hand-held, low-voltage diagnostic devices for measuring selective tissue conductance, and optionally other physiological parameters, for the sympathetic sudomotor assessment of autonomic nerve function (and dysfunction), as well as software and hardware systems and methods associated therewith that enable monitoring, objective evaluation and assessment of sympathetic and parasympathetic nervous systems, which, in turn, can be used to identify and characterize an underlying, often asymptomatic, injury, disease or disorder and determine an appropriate therapy.

Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, the preferred methods, devices, and materials are now described. However, before the present materials and methods are described, it is to be understood that the present invention is not limited to the particular sizes, shapes, dimensions, materials, methodologies, protocols, etc. described herein, as these may vary in accordance with routine experimentation and optimization. It is also to be understood that the terminology used in the description is for the purpose of describing the particular versions or embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs. However, in case of conflict, the present specification, including definitions below, will control. Accordingly, in the context of the present invention, the following definitions apply:

A. Definitions

As used herein and in the appended claims, the singular forms “a”, “an” and “the” include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to a “molecule” is a reference to one or more molecules and equivalents thereof known to those skilled in the art, and so forth.

The term “proximal” as used herein refers to that end or portion which is situated closest to the user of the device, farthest away from a target site on the subject's body. In the context of the present invention, the proximal end of the selective tissue conductance meter for sympathetic sudomotor assessment of the present invention includes the handle portion.

The term “distal” as used herein refers to that end or portion situated farthest away from the user of the device, closest to the a target site on the subject's body. In the context of the present invention, the distal end of the selective tissue conductance meter for sympathetic sudomotor assessment of the present invention includes the electrode head.

The terms “lengthwise” and “axial” as used interchangeably herein to refer to a direction relating to or parallel with the longitudinal axis of a device. The term “transverse” as used herein refers to a direction lying or extending across or perpendicular to the longitudinal axis of a device.

The term “lateral” pertains to the side and, as used herein, refers to motion, movement, or materials that are situated at, proceeding from, or directed to a side of a device.

The term “medial” pertains to the middle, and as used herein, refers to motion, movement or materials that are situated in the middle, in particular situated near the median plane or the midline of the device or subset component thereof.

As discussed above, the present invention relates to an apparatus, system and method for correlating electrical tissue parameters, such as skin conductance, with sympathetic and parasympathetic nerve function (and dysfunction) so as to provide a quantitative measurement for and sudomotor assessment of the presence and severity of corporeal pain. Of particular interest to the present invention is the measurement of absolute selective tissue conductance (STC) values. In the context of the present invention, the STC value corresponds to the galvanic skin response (GSR) or electro-dermal response (EDR), which are known to be analogous or proportional to the expected sympathetic sudomotor activity level for the site being measured at a given time. By comparing individual (absolute) STC values to other surrounding or distant (or analogous control values), sites of STC asymmetry can be identified, assessed and characterized.

As used herein, the term “tissue” refers to biological tissues, generally defined as a collection of interconnected cells that perform a similar function within an organism. Four basic types of tissue are found in the bodies of all animals, including the human body and lower multicellular organisms such as insects, including epithelium, connective tissue, muscle tissue, and nervous tissue. These tissues make up all the organs, structures and other body contents. While the present invention is not restricted to any particular soft tissue, aspects of the present invention find particular utility in the analysis of dermal and epidermal tissues to assess nerve injury, particularly peripheral nerve damage to the neck, back, limbs and extremities. The invention also finds utility in the assessment of chronic or acute odontogenic and/or orofacial pain and the oral/dental disorders associated therewith, examples of which include, but are not limited to, pericoronitis, temporomandibular joint dysfunction (TMD), and periapical periodontitis (owing to apical infection or postendodontic therapy of high occlusal contact).

The instant invention has both human medical and veterinary applications. Accordingly, the terms “subject” and “patient” are used interchangeably herein to refer to the person or animal being treated or examined. Exemplary animals include house pets, farm animals, and zoo animals. In a preferred embodiment, the subject is a mammal, more preferably a human. In that the instant invention allows for objective characterization of subject pain, it finds particular utility in connection with non-verbal human and animal subjects, including humans suffering from autism and dementia, comatose and anesthetized subjects, patients with speaking, hearing and/or comprehension disabilities, and the like.

The human nervous system is made up two parts: the central nervous system (CNS), made up of the brain and the spinal cord, and the peripheral nervous system (PNS), which consists mainly of nerves and ganglia. The CNS integrates information it receives from, and coordinates and influences the activity of, all parts of the body. The PNS on the other hand connect the CNS to the limbs and organs, essentially serving as a relay between the brain and spinal cord and the rest of the body.

The PNS is divided in the somatic nervous system, which controls voluntary action, and the autonomic nervous system, which controls involuntary action. The autonomic nervous system (ANS) acts largely unconsciously and regulates bodily functions such as the heart rate, digestion, respiratory rate, pupillary response, urination, and sexual arousal and is the primary mechanism in control of the fight-or-flight response. Autonomic functions include control of respiration, cardiac regulation (the cardiac control center), vasomotor activity (the vasomotor center), and certain reflex actions such as coughing, sneezing, swallowing and vomiting.

The ANS has three branches: the sympathetic nervous system (SNS), the parasympathetic nervous system (PNS), and the enteric nervous system (ENS). Whereas the PNS is responsible for stimulation of “rest-and-digest” or “feed and breed” activities that occur when the body is at rest, especially after eating, the primary purpose of the SNS is to stimulate the body's “fight-or-flight” response, a term that encompasses a wide range of physical and physiological reactions to stress and injury, from accelerated heart and lung action to constriction or dilation of the blood vessels to paling or flushing or perspiration.

The ANS communicates through two main neurotransmitters: acetylcholine and norepinephrine (also known as “noradrenaline”). Acetylcholine is the pre-ganglionic neurotransmitter for both the SNS and PNS divisions of the ANS, stimulating the post-ganglionic and S fibers in the autonomic ganglia. In response to such stimulation, post-ganglionic parasympathetic neurons generally release acetylcholine and thus are referred to as “cholinergic” nerves. In contrast, most post-ganglionic sympathetic neurons release norepinephrine (or noradrenaline) to act on andrenergic receptors and thus are referred to in the art as “andrenergic” nerves. The exceptions to this are the sympathetic innervation of the eccrine sweat glands and some blood vessels that remain cholinergic

The P and S branches work together to control and coordinate virtually all cells and systems within the body. The primary function of the two is to find a means of maintaining homeostasis and normal function, even in the fact of disease and end-organ dysfunction. This compromise equilibrium is achieved heartbeat by heartbeat and breath by breath. Therefore, measuring P and S activity provides additional information documenting an individual's underlying physiology (and potential pathology), enabling greater insight into disease processes, disorder, and patient response to genetic predispositions, therapy and lifestyle.

Like the rest of the nervous system, P and S neurons are plastic: they “remember” situations and “learn” about (adapt to) new situations. Injury and/or disease can cause an adaptation to a dysfunctional state. Certain therapies, from medical and surgical intervention to lifestyle modifications, will directly or indirectly affect the P and S, effectively “retraining” the P and S to yet another new state, either to support a cure, to minimize morbidity or mortality or to minimize dosing in maintenance therapy. Accordingly, measurements of P and S response to disease, and then to therapy, enables documentation of patient responses to both and titration of therapy specific for an individual patient. Of critical importance to the present invention, independent, simultaneous measures of P and S function offer quantitative documentation of clinical trending not available with current non-invasive measures of autonomic function, such as heart rate variability or beat-to-beat blood pressure monitoring. Since symptoms do no manifest until end-organ effects, early autonomic dysfunction is asymptomatic. Typically, by the time symptoms manifest (due to the beginnings of end-organ failure), advanced autonomic dysfunction or autonomic neuropathy or autonomic failure has already occurred. Thus, detection autonomic dysfunction can serve as an early stage indicator of disease.

To date, independent, simultaneous P and S assessments have been difficult to obtain clinically. The present invention addresses this deficiency by providing an apparatus, system, and method that utilizes electrical tissue parameters, such as skin conductance and resistance, as an index of autonomic nerve function and thus enables the objective evaluation of autonomic dysfunction.

To that end, the present invention describes the measurement and assessment of electrical characteristics of living tissue that, in turn, may be correlated to sympathetic and parasympathetic nerve function (and dysfunction). Examples of such measurable electrical characteristics contemplated by the instance invention include, but are not limited to, skin conductance and skin resistance. It is well-accepted that moist skin is associated with the ability to conduct electricity more readily than dry skin, the former having a lower resistance to electrical flow. When the nerve supply to the skin is interrupted, either in the context of a physical injury or a degenerative disease condition, skin moisture drops, conductance falls, and skin resistance levels rise.

In the context of the present invention, the use of conductance as the electrical characteristic to be measured has a distinct advantage over the use of resistance because the relationship between conductance and nerve function is a direct relationship rather than an inverse relationship. As such, skin conductance measurements are easier to quantify, transduce, and correlate nerve function.

As noted above, the present invention is based on the combined principles of instrumentation and the electrophysiological effects of innervation of the sweat glands. This provides a noninvasive, painless instrument system for the quantitative measurement of selective tissue conductance”, which is operationally defined herein as the relative ability of biological tissue to conduct a low voltage electrical signal, which is applied for a pre-determined period of time to a selected, limited, and restricted surface area of that tissue, and which shares those same neuroanamatomic reflex pathways as other tests of sympathetic skin activity or regional perspiration levels.

In addition to sympathetic and parasympathetic nerve function, the electrical measurements can be correlated to other physiological parameters, examples of which include but are not limited to, heme concentration, which, in turn, may be correlated to increased or decreased blood flow. Furthermore the electrical measurements can be correlated to the measurement of cell surface cytokine production as measured by the alternative embodiments of the device, e.g., in the form of an adaptable surface head.

The present invention contemplates the simultaneous measurement of other physical parameters, including, for example, temperature, pressure, oxygen saturation, glucose levels, narcotic levels, etc. Accordingly, in the context of the present invention, the testing head of the diagnostic device of the present invention may incorporate additional sensing components to allow for the measurement and recording of multiple parameters at once. Illustrative examples of such additional sensing components include, but are not limited to, thermocouples or equivalent sensors for measuring skin temperature; thermography cameras, optical infrared scanners, or ultrasonic sensors transducers for deep tissue visualization; sweat-based glucose concentration electrodes and pulse-oximeters, as well as cell surface cytokine measurement devices.

The present invention makes reference to an “electrode”, more particular a “bipolar electrode assembly” for identifying local variances in skin conductance levels as an indication of sympathetically mediated or maintained pain. In the context of the present invention, the bipolar electrode assembly is comprised of a pair of concentric or otherwise aligned electrode surfaces wherein one effectively functions as the “active” electrode while the other functions as the “return”. As used herein, the term “active electrode” refers to one or more conductive elements formed from any suitable metallic material, such as stainless steel, nickel, titanium, tungsten, and the like, connected, for example to a power supply and capable of generating an electric field. As used herein, the term “return electrode” refers to one or more powered conductive elements to which current flows after passing from the active electrode(s) back to the power source. This return electrode is located in close proximity to the active electrode and is likewise formed from any suitable electrically conductive material, for example a metallic material such as stainless steel, nickel, titanium, tungsten, aluminum and the like.

In order to avoid shorting, the two electrodes must be separated by a suitable non-conductive spacer fabricated from a suitable dielectric materials such as hard rubber joined to the electrodes via an epoxy.

In a preferred embodiment, the “active” and “return” components of the bipolar electrode assembly are concentrically situated and separated by an appropriate annular spacer. However, other shapes and configurations are contemplated by the present invention. Accordingly, the central contact, the annular spacer, and the outer electrode can have any shape, such as that of a circle, oval, triangle, square, rectangle or other regular, preferably closed polygon. The surface areas of the respective components can likewise vary, from smooth and planar to contoured, ridged or ribbed. However, it is preferred that the geometric centers of the respective components should be common or identical, i.e., “concentric”.

In the context of the present invention, measured skin conductance parameters are compared against one or more reference points to identify areas of asymmetry, which, in turn, can be indicative of an autonomic nerve imbalance. The reference point(s) for asymmetrical location identification may be provided by (a) the subject in real-time, e.g., a mirrored bilateral equivalent (e.g., left leg vs. right leg) or adjacent tissue (e.g., upper thigh vs. lower thigh); (b) a prior reading for the same subject (e.g., from a previous assessment, potentially before the onset of therapy); (c) readings from other similarly situated subjects or other positive control population; and/or (d) readings from “normal” (e.g., pain-free) subjects as negative control. The present invention refers to “normative data sets” to be used as a comparison point to identify relative high or low STC values, that are, in turn, associated with pain and/or sympathetic dysfunction.

In the context of the present invention, “normative data” is data from a reference population that establishes a baseline distribution for a score or measurement, and against which the score or measurement can be compared. Normative data is typically obtained from a large, randomly selected representative sample from the wider population.

The present invention makes reference to a device housing that contains the requisite power and circuitry components to enable activation of the one or more sensor head components and transduction of their respective signals to an output that may be correlated to pain, abnormal sensation, or sympathetic nerve dysfunction. Illustrative examples of suitable circuitry are described in U.S. Pat. Nos. 4,697,599 and 5,897,505, the contents of which are hereby incorporated by reference in their entirety.

The present invention involves the collection, storage and analysis of patient data, including measured selective tissue conductance values that find particular utility in connection with the evaluation and assessment of autonomic nerve function and/or corporeal pain levels. In the context of the present invention, collected data is held in an electromagnetic or optical form for access by a computer processor. Illustrative examples of suitable electromagnetic and optical storage media include, but are not limited to, magnetic tape; magnetic disks; optical discs such as CDs, DVDs, and Blu-ray disks; flash memory; main memory (e.g., dynamic RAM); and cache memory. The present invention contemplates data storage at both the local level (e.g., in the device housing or sensor head itself, in a smartphone, tablet, laptop, desktop or LAN computer) and at the remote level (e.g., a cloud-based database).

Data collection occurs at the sensor head which, as noted above, may be mounted to and demounted from the device housing or, alternatively, may be a separate component, optionally including its own power source and circuitry, that can communicate with, an optionally attach to, any number of devices and systems, both local and remote. For example, the sensor head may comprise a small, single-function or multi-functional electrode that may be worn by the subject either continuously or during periodic monitoring sessions. Accordingly, the sensor head may be optionally coupled with a strap, band or other support to enable proper positioning and alignment on the body.

Measurement data collected by the sensor head may be managed and processed on local processing and interface components, such as a smartphone or tablet application or “app”, or, alternatively, on a secure cloud server synchronized with to the smartphone app or other processing component (e.g., a laptop or LAN computer).

In the context of the present invention, the associated “app” should be compatible with and operational on a wide range of phone and computer-based operating systems (e.g., Mac, Windows, Apple, Android, Linux, Unix, etc.) and preferably include a simple user-interface and several key data entry and display features such as discussed in the Examples below.

The present invention contemplates two-way communication between sensor head and the hand-held device, smartphone, tablet, laptop, and/or remote server. For example, the sensor head may send raw data to the “app”, which, in turn, may analyze the data and prepare and forward a report to remote server, which, in turn, may then be reviewed by remote medical practitioner who then may send instructions for a particular therapy back down to the “app”. In that patient data is highly personal and sensitive, all communication is preferably encrypted prior to transmission. Encrypted data may be uploaded to the server for processing whenever a mobile broadband or secure Wi-Fi connection is available.

In the context of the present invention, the term “medical practitioner” refers to a health professional from the fields of dentistry, medicine, nursing, occupational health, and physical therapy, examples of which include, but are not limited to medical doctors, physician's assistants, registered nurses, nurse practitioners and LPNs, medical technicians, occupational therapists, and the like. However, the present invention contemplates reliance on artificial intelligence (AI), instead of or in addition to human practitioners, to act on the “cloud based” data platform for analytics, clinical, and research uses to enhance, refine, and make recommendations of therapies. Such AI systems may also be used to identify or pre-screen for future ailments based on the data driven to the platform.

The apparatus, system and method of the present invention finds utility in connection with “open-loop”, “semi-closed-loop” and “closed-loop” treatment and therapeutic regimens. In the context of the present invention, “open-loop” treatment refers to a regimen in which an a priori fixed dosage (or treatment regimen) is prescribed to a patient. In contrast, “closed-loop” treatment allows for dosages to be adjusted according to results obtained by laboratory analysis. The term “semi-closed loop” refers to an intermediate process having both fixed and dynamic components. Accordingly, the present invention finds utility in connection with both open-loop/fixed protocols, e.g., wherein a particular measurement results in the recommendation of a particular pain medicine, and closed-loop/dynamic protocols, e.g., wherein hour-to-hour or day-to-day variations in certain measurements result in revisions to the prescribed therapy, ranging from a new dosage to a new class of pharmaceutical to a recommendations for physical therapy or surgical intervention.

B. Pain Assessment Utilities

There are a number of significant real-world applications for an apparatus, system, and method that allows for the automated measurement and objective determination of not just the location but also the degree of corporeal pain, and thus the severity of the underlying injury, disease or disorder, such as presently disclosed.

For example, the methods of the present invention, wherein measured pain data is referenced, analyzed and quantified, find utility in the assessment of nerve injuries. Accordingly, the methods of the present invention may be applied to the evaluation of abdominal dysfunction in adults with diabetic autonomic mesenteric neuropathy and the transaxial STC imaging of regional abdominal dysfunction. Other applications of the STC analysis of the present invention include:

-   -   detecting regional autonomic dysfunction in aphasic or         non-communicating nursing home residents;     -   analyzing differences in unilateral STC to discriminate among,         diagnose and treat transient ischemic attacks (“TIA”),         reversible ischemic neurological deficits, and completed         unilateral hemispheric stroke;     -   analyzing STC regional differences to discriminate among,         diagnose and treat various forms of migraine, cluster, tension,         and other headache types;     -   sympathetic tracking in wound healing with or without subsequent         development of regional pain;     -   post-traumatic evaluation of symptoms not otherwise detectable         by standard diagnostic imaging procedures.

The apparatus, system and method of the present invention also find utility as an alarm system for children with intractable nocturnal enuresis (i.e., bed wetting).

Through the methods of the present invention, an underlying pathology, whether due to injury, illness or disease, may be objectively diagnosed, treated and monitored over time to determine progress. Periodic measurements may allow for one therapy to be measured against another. For example, the present invention provides objective criteria for comparing the efficacy of drug A against drug B to determine which best addresses a particular's subject's pain symptoms.

In addition, algorithmic analysis of baseline, bilateral and/or normative data enables to creation of a pain index, which, in turn, is highly valuable in determining a particular treatment protocol or regimen. The present invention further finds utility in the real-time quantification of pain, not only to determine the appropriate therapy but to discriminate legitimate pain patients from drug-seekers.

C. Autonomic Dysfunction Assessment Utilities

There are a number of significant real-world applications for an apparatus, system, and method that allows for the automated measurement and objective determination of not just the presence but also the degree of autonomic dysfunction (AD) and/or autonomic neuropathy (AN), and thus the severity of the underlying injury, disease or disorder, such as presently disclosed.

Autonomic decline and dysfunction generally begins before end-organ symptoms appear and thus can serve as an early indication of disease. If detected early enough, parasympathetic (P) and sympathetic (S) nerve imbalance may be corrected and corrected imbalance can prevent or retard the onset of end-organ dysfunction. Given the criticality of early diagnosis to successful treatment and/or cure, non-invasive, quantitative measurement and monitoring autonomic function or dysfunction commensurate with the present invention can improve patient outcomes and reduce healthcare cost, by reducing medication load and hospitalizations along with morbidity and mortality risks.

Table 1 below presents normal or expected vs. abnormal results of P and S activation:

TABLE 1 Organ system, organ or tissue Sympathetic activation Associated SNS disorders Parasympathetic activation Associated PSNS disorders Brain Arousal Hyperactivity Induce sleep Depression Hypothalamus — — Activate Growth and development Eyes Pupil dilation — Pupil constriction — Lachrymal — — Tearing — Salivary glands — — Salivation Sjögren's disease Thyroid Increase Hyperactivity Decrease Hypoactivity Heart - inotropy Increase High BP Decrease Low BP Chronotropy Increase Tachycardia Decrease Bradycardia Lungs - bronchi Increase = constriction Increase = asthma, COPD — — Decrease = dilation — Ventilation — — Increase = slow breathing Increase = hypoxia Decrease = fast breathing Decrease = short of breath Upper GI — — Increase = more motility Increase = GERD (overactivity) Decrease = less Motility Decrease = GERD (underactivity), gastroparesis Lower GI — Irritable bowel syndrome^(a) Increase = more motility Increase = diarrhea Decrease = less motility Decrease = constipation Pancreas (islets of Increase insulin Shock or Decrease Diabetes Langerhans) Coma Insulin Mellitus Liver Release glucose and nutrients Hyperactivity Store glucose and Hypoactivity nutrients Splanchnic system — — Increase = open Hypovolemia Decrease = close — Adrenal glands Increase = release catecholamines Increase = hyperactivity — — Decrease = store catecholamines Decrease = hypoactivity Kidneys Decrease volume Dehydration Increase volume Hyperhydration Angiotensin-renin Increase = more volume, thirsty Increase = hypertension — — Decrease = less volume Decrease = hypotension Bladder Increase sphincter tone Persistent full feeling Decrease sphincter Frequent urination tone - voiding Sex function - female Orgasm — Vaginal lubrication — Estrogen Increase ? Decrease Perimenopause Sex function - male Ejaculation Premature ejaculation, Erection No ejaculation impotence Testosterone Increase Rage Decrease Impotence Peripheral vasculature Increase = vasodilation Increase = hypertension — — Decrease = vasoconstriction Decrease = hypotension — — Sweat glands Increase = sweating, reduce core Increase = hyperhidrosis — — temperature Decrease = conserve core Decrease = anhidrosis — — temperature ^(a)Irritable bowel syndrome (IBS) involves pain which leads to SNS overactivation secondary to IBS

Autonomic dysfunction (AD) is known to precede autonomic neuropathy (AN), which, in turn, precedes chronic disease. AD and AN are mostly asymptomatic due to the simple fact that symptoms are primarily a function of end-organ dysfunction. The P and S control the organs. Between the two branches, the ANS will find a strategy to maintain homeostasis for up to decades prior to end-organ failure and symptom presentation. AD and AN are characterized by autonomic imbalance. Autonomic imbalance (AD or AN) accelerates the onset of end-organ failure and the presentation of symptoms. Chronic disease is known to lead to AN. Therefore, chronic disease, which causes autonomic imbalance, causes AD. The asymptomatic nature of AD and AN leaves only the chronic disease itself as the indicator. However, P and S monitoring allows for the early detection and clinical following of patients at the AD stage, before the onset of AN and chronic disease, both of which, unlike AD, tend to be irreversible. Through P and S monitoring, ANS imbalance may be detected and often times restored or normalized, thereby slowing or staying the onset of AN. Even after the onset of AN, normalizing an ANS imbalance can slow the progression of AN by limiting the morbidity and mortality risk, optimizing quality of life longer and promoting longevity. Establishing and maintaining a normal ANS balance can also reduce secondary symptoms, which reduces medication load, prevents hospitalization and thereby lowers healthcare costs.

Together, P and S control or coordinate all organs and organ systems within the body (see Table 1 and FIG. 29). The PNS and the SNS will work together to maintain homeostasis, even when degraded due to age, illness, etc. Since symptoms do no manifest until end-organ effects, early autonomic dysfunction is asymptomatic. Typically, by the time symptoms manifest (due to the beginnings of end-organ failure), advanced autonomic dysfunction or autonomic neuropathy or autonomic failure has already occurred. Thus, detection autonomic dysfunction can serve as an early stage indicator of disease.

Examples of diseases and disorders characterized by ANS imbalance and thus diagnosable through P and S monitoring are described by Joseph Colombo et al., in their book “Clinical Autonomic Dysfunction” (Springer International Publishing, Switzerland, 2015), the contents of which are incorporated by reference herein. As discussed therein, particularly in Appendix B, P and S monitoring finds utility in both proactive patient management and treating existing diseases or disorders including, for example, psychological and neurochemical disorders such ADD/ADHD, anxiety, bipolar disease, depression; coronary disorders such as angina, coronary artery disease (CAD), atherosclerosis, cardiac dysrhythmias, cardiomyopathy, congestive heart failure, acute and post myocardial infarction, tachycardia; respiratory disorders such as asthma and COPD; gastrointestinal disorders such as gastroparesis; and other localized and systemic disorders such as diabetes, chronic hypertension, chronic fatigue syndrome, edema, vertigo, fibromyalgia, Parkinson's disease, polyneuropathy, renal failure, sleep disorders, syncope and collapse, tension headache, and thyroid disease.

The objective evaluation of autonomic nerve dysfunction through P and S monitoring in accordance with the present invention may be optionally coupled with analyses of other physiological parameters. Such augmentative testing is described by Colombo et al. in Appendix C (page 421-426) of the above-mentioned book, “Clinical Autonomic Dysfunction”, the contents of which are incorporated by reference herein. Illustrative examples include, but are not limited to, ambulatory blood pressure, beat-to-beat blood pressure, ankle-brachial index, biofeedback, cardiac output, EKG, event monitoring, holter monitoring, nerve conduction velocity (NCV), pulmonary function testing, Q-SART (q-sweat), sitting-standing blood pressure, cardiac stress test, ST segment depression, microvolt T wave alternans, thermal studies, tilt studies, vascular imaging, respiratory activity, and vestibular testing.

FIG. 30 depicts four P and S imbalances; these are the only four abnormal autonomic states. Therapies that may be serve to rectify, ameliorate, and/or moderate an abnormal autonomic state and/or an ANS imbalance are described by Colombo et al. in Appendix A (pages 409-411) of the above-mentioned book, “Clinical Autonomic Dysfunction”, the contents of which are incorporated by reference herein. Illustrative examples include, but are not limited to, those set forth in Table 2 below, excerpted from page 88 of Dr. Colombo's book. However, other suitable interventions may be known and available to those of skill in the art.

TABLE 2 Most Frequently used drug categories for P and S therapy Agent classification Associated nervous system Primary site of action Primary effect Beta-1 adre

 antagonists Sympathetics↓ Heart ↓Heart rate (“beta-blockers”) Angio

-

 antagonists Sympathetics↓ Kidneys ↓Blood pressure (e.g., ACE-

 ARB

) Calcium channel blockers Sympathetics↓ Heart ↓Blood pressure Alpha-adrenergic antagonists Sympathetics↓ Peripheral vasculature ↓Blood pressure (“alpha-blockers”) Cholinergic antagonists (“anticholinergics,” Parasympathetics↓ Entire body ↓Parasympathetic activity e.g., tricyclics, SNRIs, SSRI

) Acetylcholinesterase inhibitor Parasympathetics↑ Entire body ↑Parasympathetic activity (e.g., Mestinon [18]) Beta-2 adrenergic agonis

Sympathetics↑ Lungs ↑Air flow (e.g., bronchodil

ors) Alpha-adrenergic agonists (

opressors) Sympathetics↑ Vasculature Constrict vasculature There are only four P&S imbalances and only eight associated (general) therapy options ACE-

 angi

-converting enzyme inhibitors, ARBs angiotensia

ptake blockers, SN

 selective no

pi

ephrine

uptake inhibitors

indicates data missing or illegible when filed

Through the methods of the present invention, an underlying pathology, whether due to injury, illness or disease, may be objectively diagnosed, treated and monitored over time to determine progress. Periodic measurements may allow for one therapy to be measured against another. For example, the present invention provides objective criteria for comparing the efficacy of drug A against drug B to determine which best addresses a particular's subject's symptoms.

D. Illustrative Embodiments of the Present Invention

Hereinafter, the present invention is described in more detail by reference to the Figures and Examples. However, the following materials, methods, figures, and examples only illustrate aspects of the invention and are in no way intended to limit the scope of the present invention. For example, while the present invention makes specific reference to arthroscopic procedures, it is readily apparent that the teachings of the present invention may be applied to other minimally invasive procedures and are not limited to arthroscopic uses alone. As such, methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention.

Examples

The present invention provides a comprehensive system for the quantitative assessment of regional sympathetic sudomotor dysfunction which is useful in the objective assessment of sympathetically maintained pain syndromes as well as autonomic nerve function; a painless electrodiagnostic method requiring no sensory stimulation or subjective reports by patients; a handheld, self-powered device with an LCD display; a rapid and simple test procedure with automatic report generation; a HHSIFDA Regulatory Class II non-invasive device; and a sympathetic skin assessment approved by Medicare and most insurance companies for procedure reimbursement.

Illustrative Diagnostic Devices

An illustrative embodiment an improved meter and monitoring system of the present invention is presented in FIGS. 1-4. FIGS. 1A, 1B, and 2A respectively depict top-down, perspective, plan views of a diagnostic device (100) designed in accordance with the principles of the present invention. Device (100) includes a housing (8) fabricated of upper (11) and lower (9) portions joined at seam (13) that together enclose the requisite circuitry and on-board power source. The proximal end of the device (100) is designed be held within the user's hand and thus may optionally be provided with finger flanges or recesses (not shown) to ensure a comfortable and secure grip. The distal end of the device (100) is characterized by a projecting sensor neck (15) and sensor head (4).

As noted in FIG. 3A, the housing may be provided with a recess (52) for receiving one or more batteries. The battery recess may be accessed by removing cover (56). The cover can be securely reattached by coupling cover latch (58) with mating recess clip (54).

As noted in FIG. 3B, the sensor head (4) may be detached and reattached from the housing as needed. As demonstrated in FIG. 3C, attachment in the depicted embodiment is achieved by mating the projecting pins (62) and annular groove (64) on the sensor neck (15) with corresponding aligned recesses and annular hub on the sensor head (not shown). However, it will be readily understood by the skilled artisan that the position of the respective coordinating elements (e.g., recessed slots and grooves that mate with assorted projecting protrusions, protuberances, tabs and splines) may be exchanged and/or reversed as needed.

In a preferred embodiment depicted in FIG. 3C, the sensor head includes a pair of concentric active electrodes (2, 3) separated by an insulating ring (1). This configuration is referred to a bipolar electrode in that its functions as both anode and cathode, “active” and “return”.

An alternate embodiment of the sensor head, one tailored for veterinary applications, is depicted in FIGS. 3D and 3E. Unique to this embodiment are the plurality of projecting electrodes (20) that enable tissue contact (and thus skin measurements) through long and/or thick hair/fur. Depending on the intended subject, the tip ends of the electrode may be tapered/pointed, as shown in FIG. 3D, or more rounded, as shown in FIG. 3E. However, the size, shape, and number of such electrode tips is largely a matter of design choice and may be routinely varied as needed. Thus, alternate configurations will be readily apparent to the skilled artisan.

Additional features of the diagnostic device depicted in FIGS. 1A and 1B are discussed in detail below.

The depicted device (100) uses a direct current (DC) measurement technique. The test current of the device (100) at the sensor head (4) is preferably a very low constant current of a maximum of 10 uA distributed over a 300 mm² area of the preferred sensor head (4) for an average of a maximum of 0.03 uA/mm². As discussed in greater detail above, this aspect of selective tissue conductance technology is known as spatial selectivity. However, as also noted above, the DC measurement technique can be replaced in the inventive system with a high frequency (preferably 1-100 kHz) alternating current signal to measure the current between the electrode components.

Preferred features of the inventive diagnostic device include, but are not limited to, the following:

Measurement Range: 1-80,000 nS/cm²

Measurement Lower Limit: 1 nS/cm²

Maximum Current Density: 0.03 uA/mm² (at electrode)

Output Display: Liquid Crystal

User Interface: 6 push button switches (keys)

Audible Indicators: integral speaker (optional headphone jack)

Interface: USB

Battery: 2 disposable (non-rechargeable) AA batteries

Battery Life: 70 hours of continuous operation. About 4 months with typical usage

Electric Shock Protection: Type B

Operation Mode: Continuous

Operating Environment: 50°-95° F. (10-35° C.), 10-90 relative humidity

Shipping and Storage Conditions: −40°-70° C., 0-90 relative humidity

Accessories: disposable electrodes; headphones; and USB cable

However, it will be readily apparent that other power sources, audio outputs, interface schemes and the like are contemplated by the present invention.

Illustrative Diagnostic Kits

The diagnostic device of the present invention may be packaged as a kit along with various coordinating accessories such as depicted in FIGS. 2B, 2C, and 2D. For example, the kit may include an external audio component, such as one or more wired or wireless earphones (30), headphones or speakers (not pictured). Earphones (30) for the device (100) may be needed in locations where the ambient noise level is high. Inserting the earphone connector (32) into the corresponding jack (7) on the device housing (8) disconnects the internal speaker. Note, the volume may need to be adjusted using up/down keys (24, 26).

The kit may further include a data transfer cord, such as depicted in FIG. 2C. In the illustrative embodiment, the respective ends include a type-C USB connector (46) and a micro-USB connector (42) coupled by cable (44). However, as noted above, alternate connector-port configurations are contemplated by the present invention, examples of which include, but are not limited to, firewire, HDMI, and e-SATA systems.

The kit may further include a power source, such as a pair of disposable AA batteries (50). However, as noted above, the power source may be rechargeable, for example in the form of a rechargeable battery pack that would be provided with the requisite associated charging cradle or charging cord(s). In an alternative embodiment, the diagnostic device may be fitted with a DC power jack capable of receiving power from a low voltage DC power source. Furthermore, alternating current (AC) power may be transformed to DC power by means of a wall-mounted transformer or 9V wall charger. In this embodiment, no AC power reaches the sensing head itself, thereby reducing the possibility and severity of electrical shock.

As noted above, each sensor head (4) is preferably used only once. In particular, it is recommended that a new sensor head (4) be used on each patient. In a preferred embodiment, the sensor head is designed as a replaceable and disposable diode. Using a new “testing head” for each patient improves sensitivity, extends the life of the system and avoids the issues of sterilization and contamination. Accordingly, the aforementioned kit may further include multiple sensor heads. Each sensor head may be identical or different, tailored for single parameter or multi-parameter measurement. In a preferred embodiment, each sensor head is separately wrapped in sterile packaging.

To remove a previously used sensor head (4), hold the outer edge by thumb and fingers and turn in a counterclockwise direction. To install the sensor head (4) onto housing (8), one should first remove it from its sterile wrapper. The center contact of the sensor head (4) is then placed over pin(s) (62) and in the annular groove (64) disposed in the sensor neck (15) of housing (8) of the inventive meter 2 and turned in a clockwise direction. When first installing a new sensor head, it is recommended that the user take a few test measurements in the “Ready” mode (described below) to ensure that the sensor head (4) is functioning properly and to become familiar with the appropriate positioning of the sensor head against the skin. While the results are not dependent on the amount of pressure, given that the conductance readings are expressed in terms of square centimeters (cm²) of surface area, it is critical that the entire active surface (e.g., inner and outer electrodes, 2 and 3) be placed in contact with the skin with sufficient pressure. If the entirety of the active electrode surface is not touching the skin, the readings will be incorrect. By the same token, while too much pressure is unnecessary, too little pressure can give rise to erroneous results.

While the illustrated embodiments depict a rigid and fixed connection between sensor neck (15) and housing (8), the present invention contemplates a flexible and/or articulated joint couplings, ranging from a simple single plane hinge to a ball-and-socket joint that affords a full 360° range of motion. Such flexible couplings ensure complete contact with the skin, particularly over contoured portions of the body such as the shoulders, knees, elbows, etc.

Illustrative Pain Measurement Protocols

To take measurements with the diagnostic device (100) of the present invention, one should place the sensor head (4) against the skin area to be measured, making sure the entire active surface (i.e., electrodes 2 and 3 and insulator 1) is placed in contact with the skin. The electrode should not be rocked during testing. Apply just sufficient pressure to ensure a good contact; too much pressure is unnecessary. Listen for the confirmation tone indicating that the test measurement is complete. This step generally takes about one half second and no more than two seconds.

Pressing the “menu” key (10) allows the operator to scroll through different programmed operating modes and utilities in a loop, as illustrated in FIG. 4. Exemplary operating modes and utilities include, but are not limited to:

-   -   The Ready Mode (or Manual Mode) is used to make one or more         individual measurements and temporarily store the data. An         exemplary display screen (30) of the device (100) in Ready Mode         is illustrated in FIG. 5.     -   The Procedure Mode is used to make measurements according to         preset programmed montages and these can also be reviewed and         uploaded to a computer. An exemplary display screen (30) of the         device (100) in Procedure Mode is illustrated in FIG. 6.     -   The Review utility is used to recall measurements taken in the         procedure mode. An exemplary display screen (30) of the device         (100) in Review Mode is illustrated in FIG. 7.     -   The Clear utility is used to delete stored tests. An exemplary         display screen (30) of the device (100) in Clear Mode is         illustrated in FIG. 8.     -   The Time/Date setting utility is used to set the date. An         exemplary display screen (30) of the device (100) in Time/Date         Setting Mode is illustrated in FIG. 9.     -   The Volume utility is used to set the volume of the internal         speaker of the device (100), or alternatively the volume output         to an external audio source, such as the earphones (30). An         exemplary display screen (30) of the device (100) in Volume         Setting Mode is illustrated in FIG. 10.

Illustrative instructions for each of the above exemplary operating modes and utilities are set forth below:

Ready Mode:

The following are exemplary “Quick Instructions” in Ready Mode: First, make sure the device (100) is in Ready Mode. Second, place the distal end of the sensor head (4) against the skin and hold for half a second. Third, listen for the beep and review the measurement. Fourth, by using the Up and Down keys, 24 and 26, previous measurements can be reviewed. Exemplary “Step-By-Step Instructions” for the programmed Ready Mode are as follows:

First, toggle through the options by repeatedly pressing the “Menu” key (10) until the device (100) displays the “Ready Mode” as illustrated in FIG. 5. Second, after the distal end of the sensor head (4) (i.e., electrode assembly: elements 1-3) has been held against the skin for approximately one-half second, a tone indicates the completion of the measurement. Remove the sensor head (4) from the skin and the STC value will be displayed. Further measurements can now be performed.

Note that a Gieger type tone is also provided which is proportional to the STC values between 0 and 100 nS/cm². Any STC values higher than 100 nS/cm2 will have the same tone. The device (100) will continue to update its clicking tone but will not the display as long as the electrode is placed on the skin. This allows the user to use the instrument to scan a body region using the Gieger clicking tone to locate areas of high conductance.

The Ready Mode can be used to take any additional individual measurements by repeating Step 2. The test number assigned by the device (100) increases incrementally as additional tests are performed. In the Ready Mode, the diagnostic device (100) of the present invention will retain the measured STC values until it automatically turns off. The measurements taken in Ready Mode can be recalled for review by using the Up or Down buttons, 24 and 26.

When the power turns off or when a new mode is selected, any data previously stored while in the Ready Mode will be lost. If the Menu key (10) is accidentally pressed in Ready Mode, an Exit Yes/No prompt will display. If the “yes” key (26) is pressed, the test data will be lost and the device (100) will revert back to Ready Mode. If the “no” key (24) is pressed, the test can be continued.

Procedure Mode:

The Procedure Mode is used when choosing from as many as eighteen or more pre-programmed montages that may optionally be stored in the device (100). A sample list of pre-programmed montages is provided below in Table 2. However, the present invention is not limited to this specific set of montages and thus the device (100) may periodically be updated to incorporate additional and/or modified montages as needed. In any event, the Procedure mode is useful when focusing on a certain body region so that it is easy to do an assessment and generate a report, which will help in finding any abnormality. The Procedure Mode assists doctors in reviewing the results and in quickly generating an accurate report.

The following are “Quick Instructions” for the Procedure Mode. First, select a pre-programmed montage. Second, enter the Montage ID from Table 2. Third, take a preliminary first set of three “BioCheck” values. Fourth, take an array of thirty-six STC Values of the body region to be tested. Fifth, take a final three post-procedure “BioCheck” values.

Illustrative “Step-by-Step Instructions” for the programmed Procedure Mode are as follows:

-   -   1. Toggle through the options by repeatedly pressing the Menu         key (10) until the device (100) displays the Procedure Mode such         as depicted in FIG. 6.     -   2. At the top of the screen, a flashing message will appear         which contains a procedure code (e.g., S01 to S18), followed by         the abbreviated name of the body region to be tested. Table 3         below presents a list of the procedure codes for each of         eighteen pre-programmed montages. The abbreviated name of the         procedure and the full name of the region to be tested are also         provided.

TABLE 3 PROCEDURE CODES Preprogrammed Montages S01 UPR FACE Upper Face S02 ANT NECK Mandible & Anterior Neck S03 CHEST Chest S04 ABDOMEN Abdomen S05 C SPINE Cervical Spine S06 TH SPINE Thoracic Spine S07 LS SPINE Lumbosacral Spine S08 UPARM AN Upper Arms, Anterior View S09 UPARM PO Upper Arms, Posterior View S10 FRARM AN Forearms, Anterior View S11 FRARM PO Forearms, Posterior View S12 HANDS Hands (Palmar & Dorsal) S13 THIGH AN Thighs, Anterior View S14 THIGH PO Thighs, Posterior View S15 LOLEG AN Lower Legs, Anterior View S16 LOLEG PO Lower Legs, Posterior View S17 FEET Feet, (Plantar & Dorsal) S18 GRADIENT Linear Gradient (2 sets of 20)

-   -   3. Use the Up or Down keys (24, 26) to select the desired         procedure, then press the Enter key (28).     -   4. After selecting the appropriate preprogrammed test, the         device (100) may prompt the entry of a procedure identification         code and then switch to the Entry Mode. This feature allows the         user to enter a file or patient identification number by         pressing the Up or Down keys (24, 26) until the value for each         of the digits has been selected. After each digit is changed         from zero to its new value, press the Enter key (28).     -   5. After entering the Identification Number, the device (100)         may prompt the user to confirm the entry.     -   6. If the Identification Number is correct, press the Yes (Up)         key (26); if incorrect, press No (Down) key (24) and re-enter         the number. Once the Identification Number has been accepted,         the ID will be stored in the test data file and maintained in         the on-board memory until downloaded or transmitted to an         external storage device. The present invention contemplates both         wired and wireless connections to local, networked or cloud         storage devices.     -   7. Now the device (100) is ready to a series of preliminary         instrument test values known as “BioCheck”. While the         illustrative examples refer to Biocheck values 1, 2 and 3, it         will be readily apparent to the skilled artisan that greater or         fewer measurements may be utilized. The BioCheck confirms that         the sensor head (4) is operating properly. In the context of the         present invention, preferred BioCheck measurements made on the         right palm, left palm, and the Mid Frontal Polar Region (i.e.,         the middle of the patient's forehead). One or more measurements         must have a positive value. If all are zero, an error message         will display and will prompt the user to check the device (100)         and repeat the procedure.     -   8. After the sensor head (4) has been held against the skin for         approximately one-half second, a tone indicates the completion         of the measurement and the measured value at the time of the         tone will be entered, thus preventing the readings from being         skewed by the iontophoresis effects which, as discussed above,         may be produced by any continued application of the DC current         to the skin after the tone. The sensor head (4) must now be         removed from the skin. The display screen (30) will display a         message asking the user to indicate whether the user accepts the         value displayed. This is a double check to confirm that the         measurement was made correctly. Press the Yes (Up) key (26) or         side auxiliary keys to accept the measurement.     -   9. If the No (Down) key (24) is pressed, the data is discarded         and a new measurement can be made. It is also possible to obtain         a valid measurement that is below the threshold of 1 nS/cm².         This is observed by pressing the sensor head (4) against the         skin and not receiving a tone for an STC measurement value, and         will be entered as a zero value. Pressing the Enter key (28)         will store this value as zero and continue to the next         measurement.     -   10. Before collecting the main body of the data in the Procedure         Mode, the user is advised to make BioCheck measurements of the         right palm, left palm, and Mid Frontal Polar region. The         BioCheck measurements are taken to ensure the sensor head (4) is         working before and after a test.     -   11. The main portion of each examination consists of a series of         measurements made along a pattern of an equal number of vertical         and horizontal lines, forming a grid optionally composed of         thirty-six points. As noted above, this is referred to herein as         a “Montage”. Each of measurement site is identified by its         position on one of the horizontal rows (e.g., R1 to R6) and one         of the six vertical columns (e.g., C1 to C6). The resulting name         of each site is therefore expressed in terms of row number and         column number, e.g., R1C6. Illustrative thirty-six measurement         point grids for the exemplary preprogrammed body locations         recited in Table 1 are depicted in FIGS. 11-28 and discussed in         greater below. Note, however, that while the examples make         reference to a 6×6 matrix of 36 measurement sites, other         matrices are contemplated, including both square and rectangular         grids comprised of 3-8, preferably 4-6 rows and columns. In any         measurement set, normative data from 20 points is used to         establish a sample. Accurate diagnosis of differences in data         can be statistically inferred from this N.     -   12. After a test montage is completed, the BioCheck screen will         reappear and the biocheck measurements, e.g., of the right palm,         left palm, and forehead, should be repeated.     -   13. After all of the measurements are made, appropriate for the         procedure selected, the message “Test Done” may appear at the         top of the screen (30). This message will flash alternately with         an instruction to “Press A Key”. As soon as any key is pressed,         the procedure is closed with the measurements stored and the         function of the device (100) is returned to the Procedure Mode,         in preparation for the next test session. In this regard, it is         further noted that:         -   a. The test number increases incrementally as further tests             are performed.         -   b. Tests stored in the device (100) can be reviewed on the             device, for example on display screen (30). The test will be             identified according to the date and then the patient ID             number of the test performed that day. Each day the tests             are stored sequentially. Once the tests have been uploaded             to an external computer or database, the ID Number can be             used for identification, for example a search term to             identify previous results.         -   c. If the Menu key (10) is accidentally pressed in Procedure             Mode the Exit Yes/No prompt will display. If the Yes key             (26) is pressed the present test data will be lost and the             device (100) will revert back to Procedure Mode. If the No             key (24) is pressed, the test can be continued.     -   14. After the final measurements are made, the automatic         shutdown feature of the device (100) will turn off the power         after a predetermined idle duration, typically two to three to         five minutes.

Review Utility Mode:

To recall and review the aforementioned Procedure Mode tests stored on the device (100), the Review Utility Mode is used. Tests stored in the device (100) can be reviewed by identifying them according to the date and test number.

Exemplary “Step-By-Step” instructions for the programmed Review Utility Mode are as follows:

-   -   1. Repeatedly press the Menu key (10) until the Review display         such as depicted in FIG. 7 appears.     -   2. Use Up and Down keys (24, 26) to select the correct date and         test number for the relevant procedure desired and press the         Enter key (28).     -   3. Use the Up or Down keys (24, 26) to review the test.

Clear Utility Mode:

Exemplary “Step-By-Step” instructions for the programmed Clear Utility Mode are as follows:

-   -   1. Repeatedly press the Menu key (10) until the Clear display         such as depicted in FIG. 8 appears.     -   2. Press the Yes key (26) to erase all tests performed in the         Procedure Mode.     -   3. Press the No key (24) to erase a specific test. Use the Up         and Down keys (24, 26) to select a particular test.     -   4. Press the Menu key (10) to exit

Report Preparation:

The system of the present invention contemplates a report writing software which may optionally be included in the aforementioned kit for a diagnostic device of the present invention. As noted above, the diagnostic device (100) is used to assist the medical practitioner (physician, clinician, technician) in recording and analyzing the collected data. The report writing software extracts this information and transduces it into a consistent format in which the medical practitioner can enter his notes and/or impressions, including, for example, additional aspects of the patient's physical or psychological presentation, such as mood, range of motion, limitations, etc. For example, when the examining medical practitioner prepares a report, he or she can review the downloaded and stored procedure readings and can then enter “Indications for Referral” or “Impressions”. If a technician is preparing a test report, the “Indications for Referral” or “Impressions” fields can optionally be left blank so that the examining physician can fill in these fields.

The following is a non-exhaustive list of illustrative functions for the Report Writer Software contemplated by the present invention:

-   -   1. Downloading stored procedure readings from the device (100)         to an external device, such as a local computer. Alternatively,         the results may be imported, downloaded, copied or otherwise         transferred to a remote location, such as a remote storage         device or cloud-based database.     -   2. Preparing reports.     -   3. Saving a test report as an editable document (such as a Word         file) with an allocated filename onto a physical storage device,         such as an external hard drive, disk, or CD-ROM, or         alternatively to the aforementioned cloud database.

In a preferred embodiment, the test report may include: subject detail (patient data); indication for referral, entered by examining physician; method; result; impressions entered by examining physician; the measured STC values of the test; and the average value of the thirty-six STC measurements.

To download the collected data and test, a small USB connector, such as a mini-USB connector (42) of a USB cable (40), may be connected to the USB port (5) of the device (100) and a larger standard USB connector, such as a type-C USB connector (46) of the USB cable (40), is connected to the USB port on the practitioner's computer or external hard-drive. Alternatively, as noted above, the connection between diagnostic device (100) and remote storage and/or analysis device, such as a local or networked computer or external hard-drive or cloud database, may be wireless, e.g., over a cellular network or short-range connection such as Bluetooth®.

An illustrative overall programmed procedure for downloading the stored procedure measurements from the device (100) is as follows:

-   -   1. Make sure that the device (100) is in Ready mode.     -   2. Double click or otherwise activate the Report writer software         icon.     -   3. Connect the device 2 and the computer using the USB cable.     -   4. The device (100) will display the USB icon on its display         (30).     -   5. On the computer, click on the “Download from Device” button.     -   6. The computer screen will display those procedures stored in         the device (100).     -   7. To select a particular test to be downloaded, highlight the         test.     -   8. Click on the Download button (24).     -   9. Repeat steps 7 & 8 to download each test.     -   10. After downloading the tests required, click on the Return To         Main Menu button.     -   11. To select a particular test to be deleted, highlight the         test and click on the Delete button.

Illustrative step-by step instructions for using the programmed procedure for preparing reports are as follows:

-   -   1. Click on the “New Report” button, which starts the         preparation of a final Word report.     -   2. To delete a downloaded test from the device, select the test         to be deleted and then click on “Delete the downloaded test”.     -   3. To delete all the tests downloaded from the Epi-Scan, click         on “Delete All”.     -   4. After analyzing the recorded data by clicking on “Next»” the         programmed procedure will start preparing the test in Word         format.     -   5. Click on “«Back” to see previous screens or “Return to Main         Menu” to go back to the “Choose Patient Test” Screen.     -   6. After analyzing the recorded data by clicking on “Next»>”,         the programmed procedure will automatically start preparing the         test in the Word format.

To See the “Final Reports” Prepared in Word:

-   -   1. Click on “Open Prepared Report.”     -   2. A “Device Report” Screen will appear.     -   3. A list of the prepared tests will appear in the list box.     -   4. Double click on the prepared final Word report desired.

Data Analysis:

Internal tests of function and calibration are performed automatically at the time of setup. However, the BioCheck function in the Procedure Mode provides a real-time test of the device (100) function while making measurements on active biological tissue, i.e. glabrous skin. Since BioCheck samples are made at sites, which are physically far from each other (palms of the hands, forehead), the values obtained also give some initial information about the dynamic range of regional differences in sudomotor function.

Following the Procedure montage, discussed below and illustrated in FIGS. 11-28, allows for the creation of a matrix set of discrete measurements, each corresponding to the sympathetic sudomotor levels at each particular location. Each individual measurement reveals an absolute selective tissue conductance (STC) value, which reflects a result, which is analogous or proportional to the expected sympathetic sudomotor activity level for the site being measured at a given time. In practice, however, more valuable information can be obtained if the individual (absolute) values are compared to other surrounding or distant values in a relative manner. This approach allows high or low values to be reviewed within the context of their spatial distribution over the whole area being tested. In such a situation, excessively high or low local values (referred to herein as “asymmetries”) may be interpreted relative to their surrounding results.

Thus, in a preferred embodiment, the Procedure montages require comparison between one side of the body and the other. In any clinical, neurophysiologic or radiologic investigation of the human nervous system, the standards of practice are to answer the questions (a) where is the problem and (b) what is the problem. Humans, and indeed most animals, exhibit bilaterally symmetry. As such, all parts of the nervous system generally consist of paired structures, i.e., body areas that occur on either side of the midline, the first step in trying to localize an abnormality is to determine which side of the body has the problem. Therefore much of the analysis of data in sympathetic sudomotor assessment is based on the detection of asymmetries or differences between values measured on the left and right sides.

The values commonly obtained during sympathetic skin assessment can range widely between one part of the body and another. The main reason for this is that there are large differences in the relative density of sweat glands over different body regions. High Selective Tissue Conductance values are often found over the palms of the hands, axillae, groin, and soles of the feet, even in normal subjects.

In addition to differences between different body regions, there are also differences in sympathetic sudomotor level between subjects (patients). It is for reasons such as this that the most effective interpretation of sudomotor levels is to use the subject as his or her own control. This means that results are compared (a) between sides along horizontal lines and (b) between proximal and distal regions measured along vertical lines. Accordingly, the pre-programmed montages of the present invention are designed to incorporate at least 4 adjacent quadrants. By comparing across quadrants, the physician can identify asymmetrical reading(s) and correlate the location of such asymmetry with the degree of pain involved and thus the severity of any underlying injury, disease or disorder.

Pre-Programmed Montages:

Exemplary pre-programmed Montage Procedures, along with the corresponding body parts and locations of the measurements, are shown in FIGS. 12-28. The typical 6×6 matrix, with 6 rows and 6 columns, common to these montages, and numbering of each measurement site is illustrated in FIG. 11. For example: R2C2 is reading of location Row 2, Column 2. R6C3 is reading of location Row 6, Column 3. However, as noted above, the present invention contemplates alternative square and rectangular matrices. The key is to divide the target area into quadrants and take an equivalent number of readings at mirrored locations within each quadrant so as to allow the subject to be his or her own control, i.e., wherein comparing results between sides along horizontal lines and between proximal and distal regions measured along vertical lines to identify asymmetries.

In addition to the pre-programmed montage procedures illustrated in FIGS. 12-28, the present invention contemplates a montage is not restricted to any body area. The linear method can be analyzed in blocks or using the linear gradient technique.

Although this pattern of Sympathetic Skin Assessment is included as an S type or Standardized montage, its design is different from those established in the previous seventeen montages S01 to S17. Instead, the present montage (S18) is based upon an extension of the linear gradient method, in which measurements are made sequentially along each of two parallel lines. Since, this specific pattern lends itself to being used to compare (or transpose) gradients in sympathetic sudomotor activity, it is also known as the Gradient Transposition montage, or more simply as the Gradient montage.

Data collection for this montage consists of the same three opening (BioCheck 1, 2, 3) and closing (BioCheck 4, 5, 6) system tests that are used in montages S01 to S17. However the active portion of the assessment process is based upon making two sets of sequential measurements, located along homologous lines over each side of the body. Each of the measurement sites is referred to by a letter designating the side (L or R) and a number (01, 02, 03, etc.), indicating the position of that site in the series.

The Gradient Montage is often used when the goal of the procedure is to detect differences in values obtained at (a) opposite sides of the body and (b) adjacent sites, along longer lines of measurement, such as assessing paraspinal regions or entire limbs. It can be used to measure along lines, which run distally or proximally as long as the start points are indicated on the test report and the locations of each pair of test sites are homologous.

To perform this type of test, the S18 Gradient montage is selected from the Procedure mode. After the Identification number has been entered, the usual BioCheck 1, 2, and 3 measurements are made. Depending on the region of the body to be tested, a series of twenty sequential measurements can be made, one electrode diameter apart, along the previously selected line, but always beginning on the LEFT side (L01 to L20-L20). As soon as the test site R01 appears on the screen, begin making measurements along the same type of line on the opposite (RIGHT) side and continue at test sites R01 to R20. Complete the procedure by performing BioCheck 4, 5, and 6 measurements.

TABLE 4 L- Left side R- Right side R01 L01 R02 L02 R03 L03 R04 L04 R05 L05 R06 L06 R07 L07 R08 L08 R09 L09 R10 L10 R11 L11 R12 L12 R13 L13 R14 L14 R15 L15 R16 L16 R17 L17 R18 L18 R19 L19 R20 L20

Illustrative Autonomic Nerve Assessment Protocols

Autonomic assessment, with P and S monitoring, provides data (at low cost) similar to the data obtained from more cumbersome, costly, and physically taxing tests including, for example, 24 hour Holter monitors, stress tests, and tilt-table studies. In addition, while conventional cardiology testing only documents the function of the heart muscle itself, namely its mechanical (echoes) and electrical functions (EKGs), it does not—and indeed cannot—directly document the autonomic involvement in cardiac function, a third, often controlling component. Accordingly, P and S monitoring can be coupled with conventional diagnostics to provide this critical missing piece of information.

To that end, the inventive apparatus, system and methods for non-invasive sudomotor monitoring and assessment, described above in connection with pain monitoring, may likewise be applied to monitoring P and S activity levels via selective tissue conductance (STC), which, in turn, may serve as an index of nerve dysfunctional.

For example, periodic P and S scanning through STC can reveal autonomic involvement in arrhythmia, including atrial fibrillation, guiding therapy to reduce arrhythmia burden and minimize risk of morbidity and mortality. Interventional therapies may then be titrated until normal sympathovagal balance is achieved. This is particularly useful, especially given that reversing poor P and S results leads to improved outcomes and that slowing P and S decline reduced morbidity and mortality, improving quality of life.

Thus, the present invention is well adapted to carry out the objects and attain the ends and advantages mentioned above as well as those inherent therein. While presently preferred embodiments have been described for purposes of this disclosure, numerous changes and modifications will be apparent to those in the art. Such changes and modifications are encompassed within this invention as defined by the claims.

INDUSTRIAL APPLICABILITY

As noted previously, there is a need in the art for the quantitative assessment of corporeal pain and autonomic nerve function. The present invention addresses this need by providing an apparatus, system and method in which pain and nerve dysfunction can be evaluated and indexed to determine not only its presence and location but its severity, and thus the location and severity of any underlying disease, disorder or injury associated therewith. The quantitative pain and nerve function scales and databases developed in the course of the present invention find utility not only in the diagnosis and treatment of any underlying or associated disorder, disease or injury but also in determining the appropriate drug and dosage regimen, in distinguishing organic pain from psychosomatic pain and legitimate pain patients from drug seekers and opioid addicts, and in comparing the efficacy of different pain medications.

The disclosure of each publication, patent or patent application mentioned in this specification is specifically incorporated by reference herein in its entirety. However, nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

The invention has been illustrated by reference to specific examples and preferred embodiments. However, it should be understood that the invention is intended not to be limited by the foregoing description, but to be defined by the appended claims and their equivalents. 

1-22. (canceled)
 23. A method for calculating the intensity of P and S imbalance exhibited by a subject, wherein said method comprises the following steps: a. identify a local area of tissue to be analyzed; b. using the device of claim 21, apply the entire active surface of the sensor head to a series of aligned target sites within said local area; c. compare the absolute STC values for each target site and identify one or more sites of asymmetry; d. optionally further compare the absolute STC value obtained at said one or more sites of asymmetry to a reference STC value obtained from (a) a prior reading for said subject at said identical local area; (b) a database of STC data collected from disease and/or normal patients; or (c) a combination thereof; and e. analyzing and transducing the degree of difference between the absolute STC value at said one or more sites of asymmetry and the reference values in steps (e) and (f) to determine the presence and calculate the intensity of autonomic dysfunction exhibited at said one or more sites of asymmetry within said local area of tissue.
 24. The method of claim 23, wherein said subject is a non-human animal.
 25. The method of claim 23, wherein said subject is a non-verbal human.
 26. The method of claim 23, further comprising the step of monitoring changes in absolute STC values at said one or more sites of asymmetry over time, before, during, and after the application of a first prescribed therapeutic regimen to determine the efficacy of said first therapeutic regimen in treating the underlying sympathetic nerve dysfunction associated therewith.
 27. The method of claim 23, further comprising the step of monitoring changes in absolute STC values at said one or more sites of asymmetry over time, before, during, and after the application of a second prescribed therapeutic regimen to determine the efficacy of said second therapeutic regimen relative to said first therapeutic regimen.
 28. The method of claim 23, further comprising the step of (a) analyzing differences in unilateral STC to discriminate among, diagnose and treat transient ischemic attacks (“TIA”), reversible ischemic neurological deficits, and completed unilateral hemispheric stroke, or (b) analyzing STC regional differences to discriminate among, diagnose and treat various forms of migraine, cluster, tension, and other headache types.
 29. The method of claim 23, further comprising the step of correlating the intensity of P and S imbalance calculated in step (g) to the diagnosis of a disease or disorder selected from the group consisting of psychological and neurochemical disorders such ADD/ADHD, anxiety, bipolar disease, depression; coronary disorders such as angina, coronary artery disease (CAD), atherosclerosis, cardiac dysrhythmias, cardiomyopathy, congestive heart failure, acute and post myocardial infarction, tachycardia; respiratory disorders such as asthma and COPD; gastrointestinal disorders such as gastroparesis; and other localized and systemic disorders such as diabetes, chronic hypertension, chronic fatigue syndrome, edema, vertigo, fibromyalgia, Parkinson's disease, polyneuropathy, renal failure, sleep disorders, syncope and collapse, tension headache, and thyroid disease.
 30. The method of claim 23, further comprising the step of correlating the intensity of P and S imbalance calculated in step (g) to the diagnosis of cardiovascular autonomic neuropathy in said subject.
 31. The method of claim 23, further comprising the step of correlating the intensity of P and S imbalance calculated in step (g) to the diagnosis of endocrinal autonomic neuropathy in said subject.
 32. The method of claim 23, further comprising the step of correlating the intensity of P and S imbalance calculated in step (g) to the diagnosis of neurological autonomic neuropathy in said subject.
 33. The method of claim 23, further comprising the step of correlating the intensity of P and S imbalance calculated in step (g) to the diagnosis of pulmonary autonomic neuropathy in said subject.
 34. The method of claim 23, further comprising the step of correlating the intensity of P and S imbalance calculated in step (g) to the diagnosis of early stage arrhythmia in said subject.
 35. The method of claim 23, further comprising the step of correlating the intensity of P and S imbalance calculated in step (g) to the diagnosis of early stage COPD in said subject.
 36. The method of claim 23, further comprising the step of correlating the intensity of P and S imbalance calculated in step (g) to the diagnosis of sleep apnea in said subject.
 37. The method of claim 23, further comprising the step of correlating the intensity of P and S imbalance calculated in step (g) to the diagnosis of depression in said subject.
 38. The method of claim 23, further comprising the step of correlating the intensity of P and S imbalance calculated in step (g) to the diagnosis of vertigo, syncope, and dizziness in said subject.
 39. The method of claim 23, further comprising the steps of correlating the intensity of P and S imbalance calculated in step (g) to the diagnosis of chronic disease in said subject and the efficacy of therapies applied to said subject for the treatment of said chronic disease.
 40. The method of claim 39, wherein said chronic disease is diabetes mellitus.
 41. The method of claim 39, wherein said chronic disease is hypertension.
 42. The method of claim 39, wherein said chronic disease is heart disease. 